Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells.
Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells.
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DOI：
10.1371/journal.pone.0000392
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发表时间：
2007-04-25
期刊：
影响因子：
3.7
通讯作者：
Rosen SD
中科院分区：
文献类型：
--
作者：
Nawroth R;van Zante A;Cervantes S;McManus M;Hebrok M;Rosen SD
硫酸乙酰肝素蛋白聚糖 (HSPG) 是 Wnt 信号传导中的控制元件，它在细胞外与 Wnt 配体结合并调节其与细胞表面信号转导受体相互作用的能力。 Sulf-1 和 Sulf-2 是新型细胞外硫酸酯酶，作用于 HSPG 内部的葡萄糖胺-6-硫酸盐 (6S) 修饰，从而调节 HSPG 与各种信号分子（包括 Wnt 配体）的相互作用。新的证据表明重新激活的 Wnt 信号在包括胰腺癌在内的多种癌症中的重要性。两种 Sulf 蛋白在人胰腺腺癌细胞中表达上调，并在人胰腺腺癌细胞系中广泛表达。人细胞外硫酸酯酶 Sulf-1 和 Sulf-2 的表达增强了重建系统中的 Wnt 信号传导。测试的四种胰腺腺癌细胞系中的三种表现出自分泌 Wnt 信号传导，因为需要细胞外 Wnt 配体来启动下游 Wnt 信号传导。将这些胰腺腺癌细胞暴露于催化失活形式的 Sulf-2 或 siRNA 介导的内源 Sulf-2 沉默会抑制 Wnt 信号传导和细胞生长。其中两个细胞系中 Sulf-2 的沉默导致免疫功能低下小鼠的肿瘤发生显着减少。我们已经确定 Sulfs 是胰腺癌细胞中自分泌 Wnt 信号传导的增强剂，并证明了它们对这些细胞的生长和致瘤性的贡献。由于磺基是细胞外酶，因此它们将成为胰腺癌治疗的有吸引力的靶标。我们的结果与文献中流行的观点相反，即硫磺是肿瘤发生的负调节因子。
Heparan sulfate proteoglycans (HSPGs) are control elements in Wnt signaling, which bind extracellularly to Wnt ligands and regulate their ability to interact with signal transduction receptors on the cell surface. Sulf-1 and Sulf-2 are novel extracellular sulfatases that act on internal glucosamine-6-sulfate (6S) modifications within HSPGs and thereby modulate HSPG interactions with various signaling molecules, including Wnt ligands. Emerging evidence indicates the importance of reactivated Wnt signaling in a number of cancers, including pancreatic adenocarcinoma. Both Sulf proteins were upregulated in human pancreatic adenocarcinoma tumors and were broadly expressed in human pancreatic adenocarcinoma cell lines. Expression of human extracellular sulfatases Sulf-1 and Sulf-2 enhanced Wnt signaling in a reconstituted system. Three of four pancreatic adenocarcinoma cell lines tested exhibited autocrine Wnt signaling, in that extracellular Wnt ligands were required to initiate downstream Wnt signaling. Exposure of these pancreatic adenocarcinoma cells to a catalytically inactive form of Sulf-2 or siRNA-mediated silencing of endogenous Sulf-2 inhibited both Wnt signaling and cell growth. Sulf-2 silencing in two of these lines resulted in markedly reduced tumorigenesis in immunocompromised mice. We have identified the Sulfs as potentiators of autocrine Wnt signaling in pancreatic cancer cells and have demonstrated their contribution to the growth and tumorigenicity of these cells. Since the Sulfs are extracellular enzymes, they would be attractive targets for therapy of pancreatic cancer. Our results run counter to the prevailing view in the literature that the Sulfs are negative regulators of tumorigenesis.
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影响因子：
7.8
作者：
Ai, Xingbin;Do, Anh-Tri;Lozynska, Olga;Kusche-Gullberg, Marion;Lindahl, Ulf;Emerson, Charles P Jr
通讯作者：
Emerson, Charles P Jr
影响因子：
4.8
作者：
Dai, YM;Yang, Y;Sanderson, RD
通讯作者：
Sanderson, RD
影响因子：
15.9
作者：
Esko, JD;Lindahl, U
通讯作者：
Lindahl, U
DOI：
10.1186/bcr1604
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grigoriadis A;Mackay A;Reis-Filho JS;Steele D;Iseli C;Stevenson BJ;Jongeneel CV;Valgeirsson H;Fenwick K;Iravani M;Leao M;Simpson AJ;Strausberg RL;Jat PS;Ashworth A;Neville AM;O'Hare MJ
通讯作者：
O'Hare MJ
影响因子：
37.3
作者：
Li J;Kleeff J;Abiatari I;Kayed H;Giese NA;Felix K;Giese T;Büchler MW;Friess H
通讯作者：
Friess H